The invention relates to new biologically degradable aliphatic copolymers of the polyesteramide or polyesterurethane type. The invention further relates to a method for preparing the copolymers and to products which can be manufactured from the new copolymers.
There is a very wide variety of polymers and copolymers. Depending on their application, they may have a great diversity of properties. Especially the mechanical properties are of importance for the use of (co) polymers in end products.
Because polymeric materials in general, and plastics in particular, are used on a very wide scale, they cause an enormous waste problem. Since the environment and pollution thereof are strong issues with the general public, there has been a trend to seek new polymeric materials which may degrade in a biological environment. It has been found difficult, however, to provide polymeric materials which have a good, i.e. fast, degradation profile, and at the same time possess very good mechanical properties.
Recently, a new class of copolymers of the polyesteramide or polyesterurethane type has been disclosed in WO-A-98/00454. These copolymers are based on symmetrical, crystalline diamide-diols, diamide-diacids or diurethane-diols, together with a secondary monomer. This secondary monomer is chosen from the group of alkanediacids alkanediacid-chlorides, alkanediols, poly(alkane ether)diols, hydroxy acids (lactones), diisocyanates and combinations thereof.
Although this new class forms a relatively successful attempt at providing a polymeric material having both good mechanical properties and degradation properties, there still remains room for improvement. Particularly, the degradation profile of the copolymers of WO-A-98/00454 is not optimal for a sufficient fast breakdown of the material under all circumstances. This makes the copolymers less suitable for use as carriers for release of active agents, such as drugs, or as biomaterials in e.g. tissue engineering.
It is therefore an object of the invention to provide a polymeric material which shows superior degradation characteristics, without this improvement in degradation properties leading to an undesired deterioration of the mechanical properties in comparison with prior art materials.
Surprisingly, it has been found that this goal can be reached by incorporating a polyalkylene glycol component into the copolymer of the polyesteramide or polyesterurethane type disclosed in WO-A-98/00454. Accordingly, the invention relates to a new class of copolymers comprising symmetrical constant blocks (CB) and variable blocks (VB) of the formula:
xe2x80x94(CB)xe2x80x94(VB)xe2x80x94
which copolymers comprise hydrophilic blocks. The definitions of the variables are given in claim 1.
The present copolymer is thus built up from a chain of building blocks, which each in turn consist per copolymer of a block with a fixed chemical structure and therefore a constant block length (designated hereinafter xe2x80x9cconstant blockxe2x80x9d), a block with a variable chemical structure and block length (designated hereinafter xe2x80x9cvariable blockxe2x80x9d).
It has been found that the present copolymers have highly advantageous mechanical properties. Furthermore, they have very good degradation characteristics which can be controlled in a manner set forth below. More in particular, in an aqueous environment, articles of manufacture of the copolymers have been found to degrade throughout their structure, thus rendering such articles highly suitable for release of active agents.
The constant block is preferably an amide block or a urethane block. In this text, these terms may be used interchangeably. Depending on the desired properties of the copolymer, one or more types of constant block may be used within one copolymer. Variation can thus occur in the variable blocks. That is, one or more types of variable blocks can be used per copolymer. The required hydrophilic blocks, which are preferably variable blocks, offer another parameter to adjust the desired properties of the copolymer. Within one copolymer, different hydrophilic blocks may be present. These hydrophilic blocks may differ from each other chemically, in length or both. Although it is preferred that the hydrophilic blocks are variable blocks, it is also possible that the constant block is hydrophilic or comprises a hydrophilic block. In particular, it has been found feasible to incorporate polyethylene oxide (PEO) blocks in formula (2), as defined in claim 1. In this case, Z2 may comprise such a PEO block provided with suitable end groups.
The amide blocks are randomly distributed over the polymer length and the uniform block length is retained during the preparation of the copolymer. The uniformity of the urethane blocks can be disrupted by the occurrence of ester-urethane exchange reactions or by alcoholysis of the urethane block, which may result in longer urethane block lengths. The said reactions, however, were under the reaction conditions found to rapidly reach an (equilibrium) plateau value which corresponds to a maximum of 15% block of which the uniformity is lost.
The uniformity of the block length is important for a number of reasons. Uniformity of the block length induces a more rapid crystallization and give better defined lamellae thicknesses of the crystalline phase. The two effects are particularly advantageous for a faster processing and for good mechanical properties, such as a high and constant young""s modulus over a wide temperature range and a good dimensional stability. These advantageous properties were attributed to a good phase separation and a rapid crystal nucleation and/or growth.
The block length itself is particularly important for the rate of biological degradation of the constant block. Biodegradability decreases with increased molecular weight and increases with increasing hydrophilicity. The amide and urethane blocks described herein are preferably short, contain only two amide or urethane bonds per unit, are usually water soluble, are completely biologically degradable and display no toxicity.
The copolymer may be prepared by starting from suitable monomers as will be set forth below.
The monomers for the constant block are symmetrical, crystalline, water-soluble and have a chemical structure in one of the following three categories: 
in which R, Rxe2x80x2, Rxe2x80x3, Rxe2x80x2xe2x80x3 and Rxe2x80x3xe2x80x3 are the same or different and represent an H, hydrocarbyl or substituted hydrocarbyl or hydrocarbyl with protected O, N, and/or S functionality. This structure is further designated xe2x80x9cdiamide diolxe2x80x9d.
The mol weight of these monomers is preferably a minimum of (n=1 m=2; Rxe2x80x94Rxe2x80x3xe2x80x3=H)=176 g/mol and a maximum of (n=15; m=12; Rxe2x80x94Rxe2x80x3xe2x80x3=H) 685 g/mol for linear monomers without side groups of other hetero-atoms in the chain. Methyl side groups can for instance be included (Rxe2x80x2=CH3), as well as hetero-atoms in structure 1 such as for instance O.
This type of monomers can be manufactured by ring opening of lactones by a primary diamine, both in solution and in the melt, without external catalysts, as well as by condensation of a linear hydroxycarboxylic acid, or hydroxycarboxylic acid ester and a primary or secondary diamine. These possible lactones herein have the following general structure: 
in which h is 2, 3, 4 or 5, i is 1 or 2, j is 1 or 2 and each R is an H or hydrocarbyl or substituted hydrocarbyl with protected O, N, and/or S functionality with a maximum of 30 carbon atoms. Preferred lactones are those in which R is hydrogen or methyl, and lactones which are particularly recommended are xcex5-caprolactone, xcex4-valerolactone, glycolide and lactides. 
in which R, Rxe2x80x2, Rxe2x80x3, Rxe2x80x2xe2x80x3, Rxe2x80x3xe2x80x3 and Rxe2x80x2xe2x80x3xe2x80x3xe2x80x3 are the same or different and represent an H, hydrocarbyl or substituted hydrocarbyl with protected functionality. Rxe2x80x3xe2x80x3 and Rxe2x80x3xe2x80x2xe2x80x3 will usually be the same and are preferably not an H and n is preferably xe2x89xa74. This structure is further designated xe2x80x9cdiamide-diacidxe2x80x9d.
The mol weight of these monomers is preferably a minimum of (n=m=2; Rxe2x80x94Rxe2x80x3xe2x80x3=H)=260 g/mol and a maximum of (n=14; m=12; Rxe2x80x94Rxe2x80x3xe2x80x3=H)=737 g/mol for linear monomers without side groups or other hetero-atoms in the chain. Methyl side groups can for instance be included (Rxe2x80x2xe2x95x90CH3), as well as hetero-atoms in structure 2, such as for instance O.
These monomers can be manufactured by ring opening of cyclic anhydrides by a primary diamine, both in solution and in the melt, without external catalysts, as well as by condensation of a linear diacid, preferably esterified (in excess) and diamine with external catalyst. The possible cyclic anhydrides herein have the following general structure: 
in which l is 2, 3 or 4 and each R1 and R2 is an H or hydrocarbyl or substituted hydrocarbyl with protected O, N, and/or S functionality with a maximum of 30 carbon atoms. 
in which R, Rxe2x80x2, Rxe2x80x3, Rxe2x80x2xe2x80x3 and Rxe2x80x3xe2x80x3 are the same or different and represent an H, hydrocarbyl or substituted hydrocarbyl with protected functionality. This structure is further designated xe2x80x9cdiurethane-diolxe2x80x9d.
The mol weight of these monomers is preferably a minimum of (n=m=2; Rxe2x80x94Rxe2x80x3xe2x80x3=H)=236 g/mol and a maximum of (n=4; m=12; Rxe2x80x94Rxe2x80x3xe2x80x3=H)=432 g/mol for linear monomers without side groups or other hetero-atoms in the chain. Methyl side groups can for instance be included (R1xe2x95x90CH3), as well as hetero-atoms in structure 3, such as for instance O.
These monomers can be manufactured by ring opening of cyclic carbonates by a primary diamine, both in solution and in the melt, without external catalysts, as well as by reaction of a primary diamine with a linear aliphatic carbonate with alcohol end groups. The possible cyclic carbonates herein have the following general structure: 
in which k is 2, 3 or 4 and each R1, R2 is an H or hydrocarbyl or substituted hydrocarbyl with protected O, N, and/or S functionality with a maximum of 30 carbon atoms.
Preferred carbonates are those in which R1, R2 is hydrogen or methyl and particularly recommended are trimethylene carbonate, ethylene carbonate, propylene carbonate, tetramethylene carbonate and 2,2-dimethyl trimethylene carbonate.
It is also possible to make amide and urethane blocks with a plurality of reactive end groups. Use must be made herein of for instance cyclic dimers or the above mentioned cyclic lactones, cyclic anhydrides and cyclic carbonates. Two examples of such structures are:
5,5xe2x80x2-bis(oxepan-2-one) and spiro-bis-dimethylene-carbonate, (2,4,7,9-tetraoxa[5,5]undecane dione-(3,8)) 
The monomers according to the invention can be used as primary monomer in polycondensation with a wide range of possible co-reagents resulting in an extensive series of copolymers.
As has been mentioned above, the variable block is chosen from the group of alkanediacids, alkanediacid-chlorides, alkanediols, poly(alkane ether)diols, and hydroxy acids, lactones, and diisocyanates. In many embodiments it is preferred that the present copolymer comprises more than one type of variable blocks within one molecule. In such a case, it is preferred that at least one of the types of variable blocks present has a relatively low boiling point. Examples of such blocks are 1,4-butanediol and ethylene glycol. Accordingly, poly(alkane ether) diacids are suitable to form or be part of the variable block. It is an important aspect of the invention that at least some of the variable blocks are hydrophilic blocks. The term xe2x80x98hydrophilic blocksxe2x80x99 is used herein to indicate that these blocks have an overall positive dipole moment or at least readily associate with or even dissolve in water. Preferably, these blocks are polar blocks, which preferably are water soluble. It is preferred that the copolymer comprises at least 5 wt. %, more preferably at least 10 wt. %, even more preferably at least 20 wt. % of hydrophilic blocks, based on the weight of the copolymer. The upper limit of the amount of hydrophilic blocks will depend on the desired degree of degradability, the desired mechanical properties and the length of the hydrophilic blocks, but will usually be below 80 wt. %, based on the weight of the copolymer. By varying the amount and length of the hydrophilic blocks, the degradability of the copolymers can be controlled. The skilled person, on the basis of his normal skills, will be able to optimize the degradability of the copolymers, given a certain objective application.
In a preferred embodiment, the copolymers comprises polyalkylene glycol hydrophilic blocks. Preferred polyalkylene glycols are chosen from the group of polyethylene glycol, and copolymers of polyethylene glycol and polypropylene glycol or polybutylene glycol, such as poloxamers. A highly preferred polyalkylene glycol is polyethylene glycol.
The terms alkylene and polyalkylene generally refer to any isomeric structure, i.e. propylene comprises both 1,2-propylene and 1,3-propylene, butylene comprises 1,2-butylene, 1,3-butylene, 2,3-butylene, 1,2-isobutylene, 1,3-isobutylene and 1,4-isobutylene (tetramethylene) and similarly for higher alkylene homologues. The polyalkylene glycol component is preferably terminated with a dicarboxylic acid residue xe2x80x94Qxe2x80x94COxe2x80x94, if necessary to provide a coupling to the polyester component. Group Q may be an aromatic group having the same definition as R, or may be an aliphatic group such as ethylene, propylene, butylene and the like.
Preferably, the polyalkylene glycol has a weight average molecular weight of from 150 to 4000, more preferably of 200 to 1500. The weight average molecular weight may suitably be determined by gel permeation chromatography (GPC). This technique, which is known per se, may for instance be performed using tetrahydrofuran as a solvent and polystyrene as external standard.
The synthesis of the present copolymer is a two-step procedure wherein in the first step the diamide-diol, diamide-diacid (ester) or diurethane-diol is prepared and purified.
The diamide-diol for use in the preparation of the present copolymer can for instance be made by ring opening of a lactone by a diamine in stoichiometric ratio. This reaction may be performed in the melt or in solution and takes place with high yield and purity. The melting points of the monomers are dependent on the used diamine and lactone.
The diamide-diacid for use in the preparation of the present copolymer may for example be produced in solution by ring opening of a cyclic anhydride by a diamine in stoichiometric ratio, or by direct condensation in the melt of an excess of linear diacid or, preferably, dimethylester, with a diamine using a catalyst, such as Ti(OBu)4. The first route results in uniform diamide-diacid blocks in high yield and purity. Methylating of acid end groups can take place in 100% yield by direct esterification in acidic environment. The second route also results in high yield. An additional purification to remove resulting longer blocks may be necessary to obtain a uniform block length. Optimization of the procedure is as yet possible.
The diurethane-diol for use in the preparation of the present copolymer may for instance be produced in solution or in the melt by ring opening of a cyclic carbonate by a diamine in stoichiometric ratio. High yield and purity can easily be obtained. Even higher purity may be achieved by washing and/or recrystallization.
The copolymer itself may be synthesized in a second step by a standard melt-condensation procedure wherein in addition to the above stated monomers from the three different categories, monomers, or mixtures thereof, are added from the following classes:
dialcohols such as ethylene glycol, 1,4-butanediol, 1,6-hexanediol, diethylene glycol and the like;
dicarboxylic acids such as succinic acids, glutaric acid, adipic acid and the like, preferably in the associated ester form;
hydroxy acids such as xcex5-hydroxy caproic acid, glycolic acid and the like, preferably in the associated ester form;
lactones such as xcex5-caprolactone, glycolide and the like.
From these monomers, plus the desired amounts of hydrophilic blocks, the variable blocks are formed which are present in the final copolymer.
It is otherwise conceivable that a one-step procedure may be developed wherein first a diamide or diurethane block is made from the correct monomers, whereafter the above mentioned monomers, mixtures thereof, or prepolymers (e.g. oligoesterdiols) thereof, and the polyalkylene glycol are added and the polycondensation is started.
Due to its highly advantageous properties, it is envisaged that the copolymer will find use in the pharmaceutical field for controlled release of bioactive agents, such as proteins, hormones, and drugs (antibiotics and the like). In addition, the material may be used as biomaterial, e.g. in the manufacture of scaffolds for tissue engineering, of devices for suturing, of sheets for preventing tissue adhesion and/or facilitating wound recovery, and the like.
The invention will now be further elucidated by the following, non-restrictive examples.